Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).

Immune-Based Therapeutic Interventions for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive, clonally heterogeneous, myeloid malignancy, with a 5-year overall survival of approximately 27%. It constitutes the most common acute leukemia in adults, with an incidence of 3-5 cases per 100,000 in the United States. Despite great advances in understanding the molecular mechanisms underpinning leukemogenesis, the past several decades had seen little change to the backbone of therapy, comprised of an anthracycline-based induction regimen for those who are fit enough to receive it, followed by risk-stratified post-remission therapy with consolidation cytarabine or allogeneic stem cell transplantation (allo-SCT). Allo-SCT is the most fundamental form of immunotherapy in which donor cytotoxic T and NK cells recognize and eradicate residual AML in the graft-versus-leukemia (GvL) effect. Building on that, several alternative or synergistic approaches to exploit both self and foreign immunity against AML have been developed. Checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors block proteins found on T cells or cancer cells that stop the immune system from attacking the cancer cells. They have been used with limited success in both the AML relapsed/refractory (R/R) and post SCT settings. AML tumor mutational burden is low compared to solid tumors and thus, it is less likely to generate neoantigens and respond to antibody-mediated checkpoint blockade that has shown unprecedented results in solid tumors. Therefore, alternative therapeutic strategies that work independently of the T cell receptor (TCR) specificity have been developed. They include bispecific antibodies, which recruit T cells through CD3 engagement, and in AML have shown an overall response rate ranging between 14 and 30% in early phase trials. Chimeric Antigen Receptor (CAR) T cell therapy is a type of treatment in which T cells are genetically engineered to produce a recombinant receptor that redirects the specificity and function of T lymphocytes. However, lack of cell surface targets exclusively expressed on AML cells including Leukemic Stem Cells (LSCs) combined with clonal heterogeneity represents the biggest challenge in developing CAR therapy for AML. Antibody-Drug Conjugates (ADC) constitute the only FDA-approved immunotherapy to treat AML with Gemtuzumab Ozogamicin, a CD33-specific ADC used in CEBPα-mutated AML. The identification of additional cell surface targets is critical for the development of other ADC's potentially useful in the induction and maintenance regimens, given the ease at which these reagents can be generated and managed. Here, we will review those immune-based therapeutic interventions and highlight active areas of research investigations toward fulfillment of the great promise of immunotherapy to AML.

Low CD34+ Cell Doses Are Associated with Increased Cost and Worse Outcome after Tandem Autologous Stem Cell Transplantation in Patients with Relapsed or Refractory Germ Cell Tumors.

Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34+ cell doses > 5.0 × 106/kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 × 106 CD34+ cells/kg is challenging. We analyzed the effect of CD34+ cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34+ dose per transplant was 3.1 × 106/kg (range, 0.8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, 0.8 to 1.9 × 106/kg; Q2, 2.0 to 2.9 × 106/kg; Q3, 3.0 to 4.1 × 106/kg; and Q4, 4.2 to 16.0 × 106/kg. For all patients higher CD34+ cell doses were associated with significantly shorter times to neutrophil (P <.001) and platelet recovery (P <.001). For inpatient transplants higher CD34+ doses were significantly associated with shorter length of hospital stay (P <.001), fewer days of filgrastim (P <.001), i.v. antibiotic (P = .012) and antifungal (P = .03) usage; and fewer RBC (P = .001) and platelet units transfused (P <.001), resulting in overall lower cost of care (P < .001). Of the 142 planned outpatient transplants, 100 admissions were required for a median length of hospital stay of 7.0 days (range, 1 to 18). Although there was no significant difference in the rates of hospitalization between patients in different CD34+ cell dose quartiles, a significant trend was observed for shorter hospitalization (P = .01) and fewer RBC (P = .002) and platelet (P = .005) transfusions with higher CD34+ cell dose quartile. Patients receiving CD34+ cell doses in the lowest dose quartile (Q1) had significantly worse progression-free survival and overall survival compared with patients receiving higher CD34+ cell doses. Overall, resource utilization, including cost of care, is significantly reduced when patients receive higher CD34+ cell doses, indicating greater efforts to improve peripheral blood stem cell collection in this population are needed.

Chronic steroid-response pancytopenia and increased bone density due to thromboxane synthase deficiency.

Diagnosis of bone marrow failure (BMF) disorders is challenging but essential for optimal patient management. Here, we report a young adult from nonconsanguineous parents with progressive pancytopenia since childhood, bone pain, increased bone density, and haphazard ossification replacing hematopoiesis within the bone marrow. Sequencing revealed two novel biallelic variants of unknown significance within the thromboxane A synthase gene, TBXAS1 (c.266T > C; c.989T > C), bioinformatically predicted to disrupt the protein. TBXAS1 mutations result in Ghosal hematodiaphyseal dysplasia (OMIM 231095), the autosomal recessive syndrome associated with abnormal bone structure and BMF. Identification of the genetic defect prompted steroid therapy leading to resolution of symptoms.

Cyclophosphamide/fludarabine nonmyeloablative allotransplant for acute myeloid leukemia.

We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow-up of 61 months, median event-free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse.

From Boring to Bravo! Using Learning Science to Create Memorable Presentations.

The practice of oncology continues to evolve over time. Educators find themselves in a position where they are no longer able to teach a topic in its entirety. Moreover, the rapid expansion of information available through research and discovery in the field of oncology makes it difficult for learners to process the constant barrage of new content. Lecturers continue to impart knowledge using didactic techniques, often trying to include as much material as possible in the time permitted. The question becomes: In the face of an impossibly large field, how can one assist learners in learning, and retaining, what is most important? The science of learning continues to develop, and we now recognize that there are ways to teach that optimally facilitate the retention and application of knowledge. By using these strategies, educators can make it easier for learners to absorb and retain key information. This article will touch upon several such techniques: cognitive load optimization, analogy, contrasting cases, elaboration, and just-in-time telling. By applying these methods to didactic presentations, educators can ensure that their lessons are heard, understood, and ultimately transformed into something unforgettable.

A phase I trial of high-dose clofarabine, etoposide, and cyclophosphamide and autologous peripheral blood stem cell transplantation in patients with primary refractory and relapsed and refractory non-Hodgkin lymphoma.

Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m(2)/day on days -6 to -2 in successive cohorts, in combination with etoposide 60 mg/kg (day -8), and cyclophosphamide 100 mg/kg (day -6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32-67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m(2)/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = 1) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CR(U)), and 2 patients achieved a partial response, for an overall response rate of 94%. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63% (95% confidence interval [CI]: 43%-91%) and 68% (95% CI: 49%-96%), respectively. We recommend clofarabine 70 mg/m(2)/day × 5 days as a phase II dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.

Effect of Sirolimus levels between days 11 and 20 after allogeneic stem cell transplantation on the risk of hepatic sinusoidal obstruction syndrome.

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12-58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21-30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57-8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.

Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis?

Linezolid, an oxazolidinone antibiotic, inhibits bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA). We studied 3 patients who experienced lactic acidosis while receiving linezolid therapy. The toxicity may have been caused by linezolid binding to mitochondrial 16S rRNA. Genetic polymorphisms may have contributed to the toxicity in 2 patients.

Teaching the physical examination: a longitudinal strategy for tomorrow's physicians.

The physical examination is an essential clinical skill. The traditional approach to teaching the physical exam has involved a comprehensive "head-to-toe" checklist, which is often used to assess students before they begin their clinical clerkships. This method has been criticized for its lack of clinical context and for promoting rote memorization without critical thinking. In response to these concerns, Gowda and colleagues surveyed a national sample of clinical skills educators in order to develop a consensus "core" physical exam, which they report in this issue. The core physical exam is intended to be performed for every patient admitted by students during their medicine clerkships and to be supplemented by symptom-driven "clusters" of additional history and physical exam maneuvers.In this commentary, the authors review the strengths and limitations of this Core + Clusters technique as well as the head-to-toe approach. They propose that the head-to-toe still has a place in medical education, particularly for beginning students with little knowledge of pathophysiology and for patients with vague or multiple symptoms. The authors suggest that the ideal curriculum would include teaching both the head-to-toe and the Core + Clusters exams in sequence. This iterative approach to physical exam teaching would allow a student to assess a patient in a comprehensive manner while incorporating more clinical reasoning as further medical knowledge is acquired.

Histological evaluation of acute mucocutaneous graft-versus-host disease in nonmyeloablative hematologic stem cell transplants with an observation predicting an increased risk of progression to chronic graft-versus-host disease.

The incorporation of nonmyeloablative conditioning prior to the transplantation of allogeneic hematopoietic cells has emerged as an alternative to myeloablative chemo- and/or radiotherapy for the treatment of hematologic malignancies. Graft-versus-host disease (GVHD) remains a significant complication of both types of hematopoietic cell transplantation (HCT). The clinical phenomenon of late-onset (>100 days after HCT) acute GVHD recently has been described following nonmyeloablative allogeneic transplantation (NMAT); however, there has been no detailed histologic description of acute GVHD in this setting. We sought to characterize the histopathologic features of acute GVHD following NMAT. The clinical and pathologic features of 20 patients with acute GVHD following NMAT over a three-year period were reviewed. Late-onset acute GVHD was diagnosed in 10 of 20 patients with a mean onset of 109.8 days (range 8-410 days); eight (40%) of these subjects with acute GVHD also had concomitant histologic features of chronic lichenoid chronic GVHD. Cases with "composite" histologic features were more likely to progress to fully developed chronic GVHD compared to those without this finding (87.5% vs 25%, P < 0.01). These findings support the existence of late-occurring mucocutaneous GVHD after NMAT and define a strong clinical/laboratory predictor for the subsequent development of chronic GVHD. Patients with composite skin GVHD may benefit from an earlier, more aggressive immunosuppressive interventional strategy.

Reduced-intensity allogeneic hematopoietic cell transplantation: Graft versus tumor effects with decreased toxicity.

The potentially curative role of allogeneic hematopoietic cell transplantation (HCT) in neoplastic and non-neoplastic diseases is offset by the substantial risks of morbidity and mortality from complications of the intensive myeloablative and immunosuppressive preparative regimen. These regimen-related toxicities have restricted allogeneic HCT to young, otherwise healthy individuals without comorbid diseases. Pediatric patients undergoing conventional allogeneic HCT have lower procedure-related mortality but are at risk for non-fatal late effects of the high-dose pretransplant chemoradiotherapy, such as growth retardation, sterility and other endocrine dysfunction. Evaluation of reduced-intensity preparative regimens is the major focus of current clinical research in allogeneic HCT. Reduced-intensity HCT (RI-HCT) relies on the use of immunosuppressive but non-myeloablative agents that allow engraftment of donor cells, which provide adoptive allogeneic cellular immunotherapy and graft versus tumor (GVT) effects, with decreased regimen-related toxicities. Although the experience with RI-HCT in pediatric patients is very limited at this time, results in adults indicate that attenuated-dose preparative regimens allow older patients and those with organ dysfunction to undergo successful allogeneic HCT with acceptable morbidity and mortality. In adults, the potency of the allogeneic GVT effect varies among neoplastic diseases, with better results observed in patients with indolent hematological malignancies or renal cell carcinoma. The effectiveness of RI-HCT as treatment for children with hemoglobinopathies, chronic granulomatous disease and cellular immunodeficiencies is encouraging, and the role of reduced-intensity preparative regimens for allogeneic HCT in pediatric malignancies is under investigation.